Rapidly disintegrating solid oral dosage forms containing dasatinib

ABSTRACT

The instant application relates to the field of pharmaceutical compositions comprising dasatinb. Furthermore, the instant application relates to a method of treating proliferative disorders in a patient in need thereof, comprising administering a therapeutically effective amount of said compositions.

RELATED APPLICATIONS

This application is continuation of U.S. patent application Ser. No.17/004,153, filed on Aug. 27, 2020, which is a continuation of U.S.patent application Ser. No. 16/700,310, filed on Dec. 2, 2019, now U.S.Pat. No. 10,799,459, which claims priority to U.S. ProvisionalApplication No. 62/849,256, filed on May 17, 2019 and U.S. ProvisionalApplication No. 62/909,913, filed on Oct. 3, 2019.

FIELD

The instant application relates to the field of pharmaceuticalcompositions comprising dasatinb. Furthermore, the instant applicationrelates to a method of treating proliferative disorders in a patient inneed thereof, comprising administering a therapeutically effectiveamount of said compositions.

BACKGROUND

Many proliferative disorders, such as tumors and cancers, have beenshown to involve overexpression or upregulation of protein kinaseactivity. Protein kinases are kinase enzymes that modify proteins bychemically adding phosphate groups (phosphorylation). Phosphorylationusually results in a functional change of the target protein by changingenzyme activity, cellular location, or association with other proteins.Protein kinases can be subdivided or characterised by the amino acids ofthe target protein whose phosphorylation they control: most kinases acton both serine and threonine, the tyrosine kinases act on tyrosine, anda number (dual-specificity kinases) act on all three. There are alsoprotein kinases that phosphorylate other amino acids, includinghistidine kinases that phosphorylate histidine residues. The humangenome contains about 500 protein kinase genes and up to 30% of allhuman proteins may be modified by protein kinases. Kinases are known toregulate the majority of cellular pathways, especially those involved insignal transduction. Dysregulation of protein kinases by mutation, generearrangement, gene amplification, and overexpression of both receptorand ligand has been implicated in the development and progression ofhuman cancers. Protein kinase inhibiting compounds or protein kinaseinhibitors (PKIs) are therefore useful for treating diseases caused byor exacerbated by overexpression or upregulation of protein kinases. Forexample, tyrosine kinase inhibitors have been shown be effectiveanti-tumor agents and anti-leukemic agents (Lowery A et. al., FrontBiosci. 2011 Jun. 1; 17:1996-2007).

Drugs that are delivered orally via a tablet should ideally be readilysoluble in water. Drugs that are poorly water-soluble tend to passthrough the gastrointestinal tract before they can fully dissolve, andthis typically leads to poor bioavailability of the drug. Unfortunately,many drugs currently on the market or in development are poorlywater-soluble, and this presents a serious challenge to thepharmaceutical industry.

A major objective of formulation chemistry is to improve drug efficacyand safety, by e.g. improving bioavailability and stability as well asconvenience to the patient. Bioavailability means the rate and extent towhich an active substance or therapeutic is absorbed from apharmaceutical form and becomes available at the site of action. Themost common and preferred method of delivery due to convenience, ease ofingestion, and high patient compliance to treatment is the oral route ofdrug delivery. However, for certain drugs, drug absorption from thegastrointestinal tract is limited by poor aqueous solubility and/or poormembrane permeability of the drug molecules.

PKIs are generally weak bases that dissolve only at low pH (e.g.100-1000 mg/L) and are practically insoluble at neutral pH (e.g. 0.1-10mg/L). Typical PKIs exhibit non-polypeptide structure and haverelatively low molecular weights, such as ≤10000 dalton or ≤5000 dalton.

pH-dependent solubility is a well-known issue for many oral formulationsof poorly water-soluble substances, such as PKIs, since most of theabsorption of the drug occurs in the small and large intestine, where pHis close to neutral. There is thus a continuing need to develop andimprove the dissolution characteristics of oral solid dosage forms ofPKI-based drugs. (Budha N R, Frymoyer A, Smelick G S, Jin J Y, Yago M R,Dresser M J, Holden S N, Benet L Z, Ware J A. Clin Pharmacol Ther. 2012August; 92(2):203-13). Furthermore, it is important that the drugreleased from the solid phase does not precipitate in thegastrointestinal tract, or precipitates as little as possible, butremains soluble in the aqueous fluids of the gastrointestinal tract,since such precipitation results in low bioavailability (see e.g. HervéJ. et al. Pharm Dev Technol. 2011 June; 16(3):278-86).

Drug absorption from a solid dosage form after oral administrationdepends on i) the release of the drug substance from the drug product;ii) the dissolution or solubilization of the drug substance underphysiological conditions; and iii) the permeation across thegastrointestinal membrane.

The Biopharmaceutics Classification System (BCS) is a system todifferentiate drugs on the basis of their solubility and permeability.

BCS Class I consists of drugs with high permeability and highsolubility. Class I compounds are well absorbed, and their absorptionrate is usually higher than excretion.

BCS Class II consists of drugs with high permeability, but lowsolubility. The bioavailability of BCS class II drugs is limited bytheir solvation rate.

BCS Class III consists of drugs with low permeability, but highsolubility. The absorption of BCS class III drugs is limited by thepermeation rate but the drug is solvated very fast. If the formulationdoes not change the permeability or gastro-intestinal duration time,then class I criteria can be applied.

BCS Class IV consists of drugs low permeability and low solubility.

BCS class IV drugs have a poor bioavailability and are usually not wellabsorbed over the intestinal mucosa and a high variability is expected.

Dasatinib monohydrate, sold under the brand name Sprycel, is classifiedas a BCS II drug, i.e. having high permeability and low solubility.Dasatinib monohydrate is also considered to be a weakly basic drug thatexhibits strong pH dependent solubility. Dasatinib monohydrate iscurrently presented in two drug product formulations, as an adultso-called immediate release tablet and a pediatric powder for oralsuspension.

Solubility class boundaries are based on the highest dose strength of animmediate release product. A drug is considered highly soluble when thehighest dose strength is soluble in 250 mL or less of aqueous media overthe pH range of 1 to 6.8 at 37° C. (Dissolution Testing and AcceptanceCriteria for Immediate-Release Solid Oral Dosage Form Drug ProductsContaining High Solubility Drug Substances; Guidance for Industry. U.S.Department of Health and Human Services Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER), August 2018). The volumeestimate of 250 mL is derived from typical bioequivalence studyprotocols that prescribe administration of a drug product to fastinghuman volunteers with a glass of water.

Most conventional so-called immediate release oral drug products, suchas tablets and capsules, are formulated to release the active drugimmediately after oral administration. Immediate-release productsgenerally result in relatively rapid drug absorption and onset ofaccompanying pharmacodynamic effects. Conventional immediate-releasesolid oral dosage form drug products containing high solubility drugsubstances are considered to be relatively low risk regarding the impactof dissolution on in vivo performance, provided the in vitro performancemeets or exceeds the recommendations set by regulatory bodies, such as,for example, the U.S. Food and Drug Administration (“FDA”) and theEuropean Medicines Agency (“EMA”).

For immediate release solid oral drug products containing a highsolubility drug substance (as defined herein), the dissolution criterionis Q=80% in 30 minutes (Dissolution Testing and Acceptance Criteria forImmediate-Release Solid Oral Dosage Form Drug Products Containing HighSolubility Drug Substances; Guidance for Industry. U.S. Department ofHealth and Human Services Food and Drug Administration Center for DrugEvaluation and Research (CDER), August 2018).

Drug product is a finished dosage form, e.g., tablet, capsule, orsolution, that contains a drug substance, generally, but notnecessarily, in association with one or more other ingredients (definedin Code of Federal Regulations Title 21, Sec 314.3(b)).

Background Regarding Dasatinib Monohydrate

Dasatinib monohydrate, sold under the brand name Sprycel, is a kinaseinhibitor indicated for the treatment of:

-   -   i) newly diagnosed adults with Philadelphia chromosome-positive        (Ph+) chronic myeloid leukemia (CML) in chronic phase. The trial        is ongoing and further data will be required to determine        long-term outcome.    -   ii) adults with chronic, accelerated, or myeloid or lymphoid        blast phase Ph+CML with resistance or intolerance to prior        therapy including imatinib; and    -   iii) adults with Philadelphia chromosome-positive acute        lymphoblastic leukemia (Ph+ALL) with resistance or intolerance        to prior therapy.

Dasatinib monohydrate (Sprycel) was approved for medical use in theUnited States and in Europe in 2006.

SPRYCEL tablets are white to off-white, biconvex, film-coated tabletscontaining dasatinib monohydrate, with the following inactiveingredients:

-   -   Lactose monohydrate    -   Microcrystalline cellulose    -   Croscarmellose sodium    -   Hydroxypropyl cellulose, and    -   Magnesium stearate.

The tablet coating consists of

-   -   Hypromellose    -   Titanium dioxide, and    -   Polyethylene glycol.        Background Regarding Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases:BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ.Based on modeling studies, dasatinib is predicted to bind to multipleconformations of the ABL kinase.

In vitro, dasatinib was active in leukemic cell lines representingvariants of imatinib mesylate sensitive and resistant disease. Dasatinibinhibited the growth of chronic myeloid leukemia (CML) and acutelymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Underthe conditions of the assays, dasatinib was able to overcome imatinibresistance resulting from BCR-ABL kinase domain mutations, activation ofalternate signaling pathways involving the SRC family kinases (LYN,HCK), and multi-drug resistance gene overexpression.

Background Regarding Dasatinib Forms

U.S. Pat. No. 7,491,725 (Bristol Myers Squibb) discloses a crystallinedasatinib monohydrate (H1-7), two crystalline anhydrate dasatinib (formN-6 and form T1H1-7), a crystalline n-butanolate (BU-2), a crystallinedi-ethanolate (E2-1), and a crystalline hemi-ethanolate (T1E2-1).

U.S. Pat. No. 7,973,045 (Teva) discloses various solvates of dasatinibsuch as an n-propanol-dimethylsulfoxide (“DMSO”) solvate of dasatinib, aDMSO solvate of dasatinib, a hemi tetrahydrofuran (“THF”) solvate ofdasatinib, a 2-methyl-tetrahydrofuran (“2-methyl THF”) solvate ofdasatinib, a hemi 1,4-dioxane solvate of dasatinib, a pyridine solvateof dasatinib, a toluene solvate of dasatinib, a methyl isobutyl ketone(“MIBK”) solvate of dasatinib, a mono acetone solvate of dasatinib, aniso-propanol (“IPA”)-DMSO solvate of dasatinib, a 2-butanol-DMSO solvateof dasatinib, an IPA-DMF solvate of dasatinib, an IPA solvate ofdasatinib, an n-propanol-DMF solvate of dasatinib, an n-propanol solvateof dasatinib, a 2-butanol-DMF solvate of dasatinib, a 2-butanol solvateof dasatinib, an n-butanol-DMSO solvate of dasatinib, a DMF-watersolvate of dasatinib, a DMF solvate of dasatinib, a methyl isopropylketone (“MIPK”) solvate of dasatinib, a dimethoxyethane solvate ofdasatinib, a cellosolve solvate of dasatinib, a methylacetate solvate ofdasatinib, a methanol solvate of dasatinib, an ethylacetate solvate ofdasatinib, a 2-pentanole solvate of dasatinib, a dimethyl carbonatesolvate of dasatinib, an isopropylacetate solvate of dasatinib, aethyleneglycol solvate of dasatinib, a dichloromethane solvate ofdasatinib, a methylformate solvate of dasatinib, a tert-butanol solvateof dasatinib, a dimethoxyethane solvate of dasatinib, amethylethylketone (“MEK”) solvate of dasatinib, a monochlorobenzenesolvate of dasatinib, a propylene glycol monoethyl ether (“PGME”)solvate of dasatinib, a glycerole solvate of dasatinib, a cyclopentylmethyl ether solvate of dasatinib, a methyl tert butyl ether (“MTBE”)solvate of dasatinib, an amylalcohol solvate of dasatinib, and aglycerol formal solvate of dasatinib.

WO 2017/002131 (MSN) discloses a 1,2-propanediol solvate of dasatiniband WO 2017/134615 (Dr. Reddy) discloses a (R) and (S)-1,2-propanediolsolvate of dasatinib.

WO 2017/144109 discloses an oral dosage form comprising dasatinibanhydrous N6 polymorph. It is further disclosed therein that when thedisintegrant content is increased within a specific range, 0.3:1.0 to0.5:1.0 based on the amount of dasatinib free base, then the dissolutionof dasatinib N6 form from the dosage form decreases.

Dasatinib can thus be considered to a promiscuous compound with a highnumber of solvates. The monohydrate (H1-7), anhydrate (form N-6),anhydrate (form B, Teva) and 1,2-propanediol solvate (MSN) have all beentested in clinical trials on human beings.

Background Regarding Generic Drugs

A generic drug must contain the same active pharmaceutical ingredient asthe original brand name product, but it may differ in characteristicssuch as manufacturing process, formulation, excipients, color, taste,and packaging.

Drug companies can submit an abbreviated new drug application (ANDA) forapproval to market a generic drug that is the same as (or bioequivalentto) the brand-name product. FDA's Office of Generic Drugs reviews theapplication to make certain drug companies have demonstrated that thegeneric medicine can be substituted for the brand-name medicine.

An ANDA must show the generic medicine is equivalent to the brand in atleast the following ways:

-   -   i) The active ingredient is the same as that of the brand-name        drug/innovator drug.    -   ii) The generic medicine is the same strength.    -   iii) The medicine is the same type of product (such as a tablet        or an injectable).    -   iv) The medicine has the same route of administration (such as        oral or topical).    -   v) It has the same use indications.    -   vi) The inactive ingredients of the medicine are acceptable.

Some differences, which must be shown to have no effect on how themedicine functions, are allowed between the generic and the brand-nameversion.

The FDA defines bioequivalence as the absence of a significantdifference in the rate and extent to which the active ingredient becomesavailable when administered at the same molar dose under similarconditions in an appropriately designed study.

In order to determine bioequivalence, a randomized, crossover trial isconducted with both the generic drug being assessed and the brand-namedrug as the control. In these studies, a number of pharmacokinetic (PK)parameters are assessed, including maximum serum concentration of a drug(Cmax) and drug exposure over time (AUC).

These parameters help assess how the rate and extent of the availabilityof the generic drug compares to the control. As the FDA requires, theremust be no significant difference in the rate and extent to be deemedbioequivalent.

According to current FDA and EMA guidance documents bioequivalence canbe declared when the 90% confidence interval for the ratio of meanvalues for Cmax and AUC for generic drug vs. original drug falls withinthe interval 80-125%, as evaluated in a randomized, cross-over trial.

The confidence interval is dependent on both the point estimate for theratio of mean values and on the variability between subjects in the PKparameter for each product. The larger the deviation in point estimatefor the ratio from the value 1.0 and the larger the variability in thePK parameter between subjects for each product, the more unlikely itbecomes that bioequivalence criteria will be met.

A ratio of mean values for Cmax and AUC for generic drug vs. originaldrug below 0.9 or above 1.1 will typically result in a 90% confidenceinterval outside 80-125% unless the variability in Cmax and AUC betweensubjects is very low. Therefore, the bioequivalence criteria are verystrict and require that both the ratio of mean values is close to 1.0and that the variability between subjects is limited.

According to an FDA study, the mean difference for AUC values betweentest and reference products was found to be 3.5% in the 2-year periodfollowing the Waxman-Hatch Act (Buehler G. History of bioequivalence forcritical dose drugs. FDA).

In other words, it is a misconception that the FDA allows the strengthof the tablet or a PK parameter, to vary from 80%-125%. The mean PKvalue of the generic drug must be quite close to that of the referencedrug for the ratio of the PK values (AUC and Tmax) to be close to 1.00which implies comparable bioavailability. If the ratio is not close to1.00, then the 90% CI of ratio is unlikely to lie between 0.80 and 1.25.

Assessment of bioequivalence (BE) for highly variable drugs ischallenging.

Reference-scaled average bioequivalence (RSABE) is a statisticalmethodology that is increasingly used to demonstrate bioequivalence forhighly variable drugs (HVDs). A drug product is called highly variableif the intra-subject (ie, within-subject) variability is greater than30% C.V. (coefficient of variation) in the pharmacokinetic measures ofAUC and/or Cmax. In other words, if you take the same drug in twodifferent occasions at similar conditions (eg, same dosage,administration route, fasted, same time a day, etc.) you would expectthe measured AUC and Cmax to be very similar regardless of the time ofadministration. However, if instead the rate and extend of absorptiondiffer by more than 30% between the occasions then the drug isconsidered highly variable. In those cases, running ABE with thestandard sample size will likely fail to show bioequivalence due to theintrinsic variability even if the products were comparable. Indeed, someHVDs have failed to show bioequivalence to itself using standard ABEsample sizes. For HVDs, studies designed to show bioequivalence may needto enroll large numbers of subjects, even when the formulationsthemselves have no significant mean differences. This increases theexpense of BE studies, places more subjects at risk, and ultimately,limits the availability of generics.

The RSABE method allows to scale the acceptance bioequivalence windowbased on the within subject variability of the reference drug. Thus, thelimits of the conventional average bioequivalence (ABE) can be scaled tothe reference variability (ie, the permitted window increases as thevariability increases). RSABE methods can be applied to showbioequivalence if the within subject variability for the reference drughas been shown to have at least 30% CV.

Specifics of RSABE methodology vary between regulatory agencies. Simplystated, the RSABE may be employed if the reference productwithin-subject variability, CV_(WR), is greater than 30%, whichcorresponds to a within-subject standard deviation S_(WR)≥0.294.

As related to AUC, if S_(WR)≥0.294, then RSABE may be permitted andacceptance criteria for 90% CI may be widened. The point estimate (orgeometric mean ratio) must be within 80-125% regardless of the widenedacceptance criteria.

As related to Cmax, if S_(WR)≥0.294, then RSABE may be permitted andacceptance criteria for 90% CI may be widened. The point estimate (orgeometric mean ratio) must be within 80-125% regardless of the widenedacceptance criteria.

In addition, most regulatory authorities would look at the intra-subjectvariability for the two products and ask questions if there was a markeddifference between them. Products satisfying the bioequivalencerequirements can reliably be assumed to produce similar clinical effectswhen used interchangeably in the same patient.

There is thus a high medical need and high commercial incentives forcompanies to develop a drug that is considered a generic drug accordingthe relevant national regulatory standards. Such regulatory standardsare high and difficult to meet since safety and efficacy is a majorconcern for all regulatory authorities. It is thus a major challenge todevelop a drug that is considered fully bioequivalent and substitutablefor the reference listed drug (RLD).

It is well established that Sprycel has a high PK variability. Lassmanet al. (Phase 2 trial of dasatinib in target-selected patients withrecurrent glioblastoma (RTOG 0627) in Neuro-Oncology, Volume 17, Issue7, 1 Jul. 2015, Pages 992-998) discloses that dasatinib exposure isknown to be quite variable within and between patients, withcoefficients of variation of up to 100% for both AUC and Cmax.

There is notable interindividual heterogeneity in drug response,affecting both drug efficacy and toxicity, resulting in patient harm andthe inefficient utilization of limited healthcare resources. It has beenreported that the proportion of patients who respond beneficially to thefirst drug offered in the treatment of a wide range of diseases istypically just 50-75%. Drug absorption is an important component of drugresponse where interindividual variability leads to patient harm and theexcessive and inefficient use of limited healthcare resources.

Background Regarding Dasatinib Bio-Equivalence Tests

The dasatinib monohydrate (H1-7) has been developed into Sprycel by BMS.All other dasatinib forms (anhydrate form N-6 [BMS], anhydrate form B,[Teva] and 1,2-propanediol solvate [MSN]) that have been tested inclinical studies for bio-equivalence vis-a-vis Sprycel have given ahigher AUC compared to Sprycel. All forms have thus failed to meet theBE-standard of the entire 90% confidence interval (CI) of the observedPK value (AUC and Cmax) to fall between 80% and 125%. However, a genericversion containing the anhydrate form N-6 was recently approved by EMAdespite having an AUC with 90% confidence interval (CI) higher than 125%compared to Sprycel. Approval was only given after excluding somepatients that showed an unexplained low exposure of dasatinib.

The Public Assessment Report on this medicinal product consisting ofdasatinib film coated tablets from Centrafarm B.V. was published byCollege Ter Beoordeling van Geneesmiddelen on 6 Dec. 2018. The PublicAssessment Report discloses the review performed on the quality, safetyand efficacy data. The crystalline N-6 form of dasatinib was used as theactive pharmaceutical ingredient (API) and the following additionalexcipients were used:

Tablet core

-   -   Cellulose, microcrystalline (E460)    -   Lactose monohydrate    -   Croscarmellose sodium    -   Hydroxypropylcellulose (E463), and    -   Magnesium stearate (E470b)

Film-coating

-   -   Poly(vinyl alcohol) (E1203)    -   Titanium dioxide (E171)    -   Talc (E553b)    -   Glyceryl monostearate (E471), and    -   Sodium laurylsulfate

The first BE study was done with a 140 mg tablet and a simple cross-overstudy with 130 individuals. The test product gave too high AUC when allindividuals were analyzed. The inter-individual was 48% for AUC and 62%for Cmax for the Sprycel tablet.

A four-way study in fasting was continued with each product given twiceat a dose of 140 mg. This study also did not show formal bioequivalence.Numerical results are not shown in the Report.

In the analysis of data, it was found that the variability of AUC wasgreater for Sprycel than for the test product since Sprycel couldprovide very low exposures in some individuals. The new product wastherefore approved by EMA despite deviation from formal BE because itgives a lower variability in AUC than Sprycel.

Vaidhyanathan et al. (Journal of Pharmaceutical Sciences 108 (2019)741-749) discloses a bioequivalence comparison of a dasatinib suspensionwith commercial tablet (Sprycel) and elucidation of absorptionmechanisms. A bioequivalence study comparing the formulations in adulthealthy subjects found that overall exposure (AUC 0-24) from suspensiontreatments was ˜9% to 13% lower, Cmax was similar, and median Tmax was˜30 min earlier vis-à-vis the tablet. To understand the mechanismcontributing to this behavior a combination of biorelevant dissolutionstudies and physiologically based pharmacokinetic modeling was used andlead to the conclusion that that the mechanism that drives the reducedbioavailability of the suspension is inherent to the in vivo gastricbehavior of the two different dosage forms. That is, the reducedbioavailability of the suspension was attributed to the shorter gastricresidence time for suspensions relative to tablet and not related to theformulation composition or other drug product attributes.

Vaidhyanathan et al. uses a dissolution test where each formulation wasintroduced into 0.1 N HCl (stage 1) for 20 min followed by a switch toFaSSIFmedia (stage 2) to mimic the in vivo gastric to intestinal pHcondition change in the fasted state. At stage 1, the test used 50 mL0.1 N HCl (pH 1.2) for 20 min and at stage 2, added FaSSIF to reach 300mL total final volume (1.2×FaSSIF preparation to accommodate dilutionfrom the 0.1 N HCl). This 2-stage test with pH shift used a UnitedStates Pharmacopeia (USP) 2 apparatus at 75 RPM and 37° C. The volume of50 mL in 0.1 N HCl followed by addition of 250 mL of 1.2×FaSSIF to reacha final volume of 300 mL was chosen to keep the volume low andapproximate biorelevant conditions (representative of the dose volumeand stomach).

Klingberg et al. (J Global Trends Pharm Sci, 2016; 7(3): 3367-3373)discloses a comparative BE study with Dasatinib tablets 140 mgoriginating from MSN Laboratories with reference formulation Sprycel®140 mg film-coated tablet after single dose administration under fastingconditions in 24 healthy adult male and female volunteers. The twoformulations were found to be non-bioequivalent since the 90% confidenceinterval for the (Test/Reference ratio) of AUC_(0-t) and C_(max) were114.29%-224.24% and 108.85%-244.36% under fasting condition. The ratioof geometric least square means for the (Test/Reference ratio) ofAUC_(0-t) and C_(max) were 160.08% and 163.08% under fasting condition.

Chandani et al. (Atypical pharmacokinetic profiles observed withdasatinib reference listed drug product in bioequivalence studies,poster M6107) discloses anomalous exposure profiles seen in small andinconsistent proportion of the panel within in-house dasatinib clinical.Overall the dasatinib product has consistently demonstrated erraticpharmacokinetic exposure profiles in 3.5%-7.5% in every in-house study,as well as very high Intra Subject Variability (ISCV) in AUC andC_(max). Chandani et al. concludes that for EU studies approximately4.5% of subject data was excluded due to anomalous profile regulations.FDA outlier test carries a far more stringent criteria for PK dataexclusion as compared to the EMA 5% rule; As a result, far fewerindividual subject data sets would qualify for data exclusion based onthe results of a studentized residuals outlier test.

There is thus an unmet need for a pharmaceutical composition that isbioequivalent to Sprycel (dasatinib monohydrate), but with fewerdrawbacks like inter- or interindividual variation, food interaction,bioavailability dependent of gastric transit time and the like.

Fish et al., J Pharm Innov (2009) 4:165-173, discloses a dissolutionmethod for Sprycel film-coated tablets. The method was developed to be adiscriminatory method that not only could assess batch-to-batchvariation but also be used to compare performance between dosagestrengths that were not used in the clinic to clinical dosage strengthsto support a biowaiver. The final validated method utilizes 1,000 mL ofpH 4.0 acetate buffer with 1% Triton X-100 with a USP Apparatus II(paddle) rotating at 60 rpm and a HPLC sample analysis. The method wasaccepted by regulatory agencies globally for registrational testing of20 and 50 mg tablets initially commercialized and has been successfullytransferred to quality control laboratories in six countries around theworld, according to the authors. The method has also been successfullyapplied to obtain biowaivers for 70 and 100 mg dosage strengths. It isthus reasonable to assume that this method would be used in producing ageneric copy of Sprycel.

SUMMARY

One aspect is directed to a pharmaceutical composition for oral usecomprising dasatinib, preferably dasatinib 1,2-propanediol solvate,dasatinib (R)-1,2-propanediol solvate, dasatinib (S)-1,2-propanediolsolvate, or a combination thereof.

One embodiment of the present disclosure provides an oral pharmaceuticalcomposition in the form of a tablet or a capsule.

One embodiment encompasses an oral pharmaceutical composition, whereinthe pharmacokinetic profile of the dasatinib is less affected by the fedor fasted state of a subject ingesting the composition compared toSprycel, in particular as defined by Cmax and AUC guidelines given bythe FDA and EMA.

The amount of dasatinib can correspond to any of commercially availabletablets sold under the trademark Sprycel, i.e. 20, 50, 70, 80, 100 or140 mg. A conversion factor must be used to calculate the specificamount of for example dasatinib 1,2-propanediol solvate, or dasatinib1,2-propanediol solvate (R) or (S) enantiomer that corresponds to 20,50, 70, 80, 100 or 140 mg anhydrous dasatinib. 115.6 mg of dasatinibpropylene glycol solvate is for example considered to be equivalent to100 mg of anhydrous dasatinib, which corresponds to a conversion factorof about 1.156.

Bioequivalence of the oral compositions of the present disclosure may beestablished by a) 90% Confidence Interval for the ratio (generic drug vsreference listed drug) of mean AUC(0-t), which is between 80% and 125%;b) 90% Confidence Interval for the ratio (generic drug vs referencelisted drug) of mean AUC(0-∞), which is between 80% and 125%; or c.) a90% Confidence Interval for the ratio (generic drug vs reference listeddrug) of mean Cmax, which is between 80% and 125%; or a combination ofany features a-c above.

Alternatively, bioequivalence of the oral compositions of the presentdisclosure may be established by (a) a 90% Confidence Interval for theratio (generic drug vs reference listed drug) of AUC(0-∞) is between 80%and 125%, and optionally without excluding any subjects with AUC(0-∞)<5%of the reference listed drug; (b) a 90% Confidence Interval the ratio(generic drug vs reference listed drug) of for Cmax, which is between80% and 125%; and without excluding any subjects with AUC(0-t).; and (c)a 90% Confidence Interval the ratio (generic drug vs reference listeddrug) of Cmax, which is between 80% and 125%; or a combination of anyfeatures a-c above.

Alternatively, bioequivalence of the oral compositions of the presentdisclosure may be established by reference-scaled average bioequivalence(RSABE) approach, whereby the BE acceptance limits are scaled to thevariability of the reference product. For both the EMA and the FDA,RSABE can be employed if the reference product within-subjectvariability, CV_(WR), is greater than 30%, which corresponds to awithin-subject standard deviation S_(WR)≥0.294. Based on theintra-subject standard deviation of the reference formulation one cancalculate the following scaled acceptance range limits:

CV_(WR) S_(WR) FDA RSABE Limits <30 ABE Methodology 30 0.29476.94-129.97 35 0.340 73.82-135.47 40 0.385 70.89-141.06 45 0.42968.15-146.74 50 0.472 65.58-152.48 60 0.555 60.95-164.08

One embodiment of the present disclosure is the first dasatinibcontaining drug product that is independent of gastric transit time.

It is also the first dasatinib containing drug product that is AB ratedtherapeutic equivalent to Sprycel (dasatinib monohydrate), i.e.pharmaceutically equivalent since it contains the same active ingredientin the same dosage form, same strength or concentration and same routeof administration, and also bioequivalent according to FDA standard.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides results of a dissolution test, a USP Type 2 in 0.01 Mhydrochloric acid at about 37° C. and about 75 RPM, of tablets preparedin Examples 1 to 13.

FIG. 2 displays the results showing comparable bioavailability betweenthe test tablet A and the reference product, Sprycel® 100 mg.

Both the foregoing general description and the following detaileddescription are exemplary and explanatory and are intended to providefurther explanation of the disclosure as claimed. Other objects,advantages, and novel features will be readily apparent to those skilledin the art from the following detailed description.

DETAILED DESCRIPTION

In one aspect there is provided a tablet for oral administration,comprising dasatinib, such as dasatinib 1,2-propanediol solvate,dasatinib (R)-1,2-propanediol solvate, dasatinib (S)-1,2-propanediolsolvate, or a combination thereof; and at least one pharmaceuticallyacceptable excipient;

wherein the tablet exhibits at least one of the followingcharacteristics:

(a) a 90% Confidence Interval for the ratio of the mean AUC(0-∞) whichis between 80% and 125%; and

(b) a 90% Confidence Interval for the ratio of the mean Cmax, which isbetween 80% and 125%;

(c) RSABE AUC criterion;

(d) RSABE Cmax criterion and;

(e) the tablet (coated or uncoated) releases at least 80% of thedasatinib within 20 minutes when the tablet is tested in a USP Type 2 in0.1 M hydrochloric acid at about 37° C.;

wherein the ratio of the mean refers to an observable of the tablet fororal administration vs. the reference listed drug (SPRYCEL® 100 mg).

In one embodiment there is provided a tablet for oral administration,comprising dasatinib, such as dasatinib 1,2-propanediol solvate,dasatinib (R)-1,2-propanediol solvate, dasatinib (S)-1,2-propanediolsolvate, or a combination thereof; and at least one pharmaceuticallyacceptable excipient;

wherein the tablet (coated or uncoated) releases at least 80% of thedasatinib within 20 minutes when the tablet is tested in a USP Type 2 in0.1 M hydrochloric acid at about 37° C.; and

wherein the tablet exhibits at least one of the followingcharacteristics:

(a) a 90% Confidence Interval for the ratio of the mean AUC(0-∞) whichis between 80% and 125%; and

(b) a 90% Confidence Interval for the ratio of the mean Cmax, which isbetween 80% and 125%;

(c) RSABE AUC criterion;

(d) RSABE Cmax criterion and;

wherein the ratio of the mean refers to an observable of the tablet fororal administration vs. the reference listed drug (SPRYCEL® 100 mg).

In one embodiment the dasatinib is in the form of dasatinib1,2-propanediol solvate.

In one embodiment the dasatinib is in the form of dasatinib1,2-propanediol solvate (R) or (S) enantiomer, or a mixture thereof.

In one embodiment the dasatinib is in the form of dasatinib1,2-propanediol solvate (S) enantiomer.

Dasatinib 1,2-propanediol solvate is also referred to as dasatinibpropylene glycol solvate.

In one embodiment the dasatinib is administered to a human subject in afasted state.

In one embodiment the dasatinib is administered to a human subject in anon-fasted state.

In one embodiment the bioequivalency is established by a 90% ConfidenceInterval for the ratio of the mean AUC(0-∞) which is between 80% and125%.

In one embodiment the bioequivalency is established by a mean forAUC(0-∞) which is between 80% and 125%.

In one embodiment the bioequivalency is established by a 90% ConfidenceInterval for the ratio of the mean AUC(0-t) which is between 80% and125%.

In one embodiment the bioequivalency is established by a mean forAUC(0-t) which is between 80% and 125%.

In one embodiment the bioequivalency is established by a 90% ConfidenceInterval for the ratio of the mean for Cmax, which is between 80% and125%.

In one embodiment the bioequivalency is established by a mean for Cmax,which is between 80% and 125%.

In one embodiment the bioequivalency is established using thereference-scaled average bioeqvivalence (RSABE).

In one embodiment the bioequivalency is established without excludingany subjects.

In one embodiment the bioequivalency is established by excludingsubjects with AUC (0-∞)<5% of the reference listed drug.

In one embodiment the bioequivalency is established by excludingsubjects with AUC (0-t)<5% of the reference listed drug.

The dasatinib compositions of the present disclosure have unexpectedlydramatic dissolution profiles. Rapid dissolution of an administeredactive agent is preferable, as faster dissolution generally leads tofaster onset of action and greater bioavailability. To improve thedissolution profile and bioavailability of dasatinib it would be usefulto increase the drug's dissolution so that it could attain a level closeto 100%.

The dasatinib compositions of the present disclosure preferably have adissolution profile in which within about 5 minutes at least about 20%of the composition is dissolved. In other embodiments of the disclosure,at least about 30%, about 40%, about 50%, about 60%, about 70%, about80%, about 90%, or about 100% of the dasatinib composition is dissolvedwithin about 5 minutes. In other embodiments of the disclosure,preferably at least about 40%, about 50%, about 60%, about 70%, about80%, about 90%, or about 100% of the dasatinib composition is dissolvedwithin about 10 minutes. In another embodiment of the disclosure,preferably at least about 70%, about 80%, about 90%, or about 100% ofthe dasatinib composition is dissolved within about 15 minutes. Inanother embodiment of the disclosure, preferably at least about 70%,about 80%, about 90%, or about 100% of the dasatinib composition isdissolved within about 20 minutes.

Dissolution is preferably measured in a medium which is discriminating.Such a dissolution medium will produce two different dissolution curvesfor two products having different dissolution profiles in gastricjuices; i.e., the dissolution medium is predictive of in vivodissolution of a composition. An exemplary dissolution medium is anaqueous medium of 0.01 M hydrochloric acid at about 37° C., under socalled USP Type 2 conditions i.e. a paddle speed of about 75 rpm in 500mL. Determination of the amount dissolved can be carried out by anystandard procedure recognized in the art.

Pharmaceutical Excipients

A pharmaceutical excipient is a substance formulated alongside theactive ingredient of a medication, included for example for the purposeof long-term stabilization, bulking up solid formulations that containpotent active ingredients in small amounts (thus often referred to as“bulking agents”, “fillers”, or “diluents”), or to confer a therapeuticenhancement on the active ingredient in the final dosage form, such asfacilitating drug absorption, reducing viscosity, or enhancingsolubility. Excipients can also be useful in the manufacturing process,to aid in the handling of the active substance concerned such as byfacilitating powder flowability or non-stick properties, in addition toaiding in vitro stability such as prevention of denaturation oraggregation over the expected shelf life.

Fillers/Binders

Fillers add bulk to tablets making small amounts active componentseasier to handle during the manufacturing process. Binders hold theingredients in a tablet together. Binders ensure that tablets andgranules can be formed with required mechanical strength and give volumeto low active dose tablets. Many pharmaceutical excipients have dualfunctionality and fillers and binders are thus often often treated asone group of pharmaceutical excipients, i.e. fillers/binders. Suitablefillers/binders are different grades of mannitol, microcrystallinecellulose, lactose, isomalt or mixtures thereof. Suitable amounts offillers/binders are about 20-90% by weight, about 30-80% by weight,about 40-70% by weight, and about 50-60% by weight.

Disintegrants

Disintegrants swell, expand and/or dissolve when wet causing the tabletto break apart in the digestive tract, or in specific segments of thedigestion process, releasing the active ingredients for absorption.Suitable disintegrants, such as croscarcellose sodium, crospovidone, andsodium starch glycolate, or mixtures thereof may be used. Suitableamounts of disintegrants are about 0.5-10% by weight, about 1-9% byweight, about 2-8% by weight, about 3-7% by weight, about 4-6% byweight, and about 5% by weight.

Glidants

Glidants are used to promote powder flow by reducing interparticlefriction and cohesion. Glidants are often used in combination withlubricants as they have small ability to reduce die wall friction. Anyconventional glidant, such as anhydrous colloidal silica may be used.Suitable amounts of glidants are about 0-5% by weight, about 1-4% byweight and about 2-3% by weight.

Lubricants

Lubricants prevent the clumping of active ingredients and prevent thesticking of materials to machines in the manufacturing process. Anyconventional lubricant, such as sodium stearyl fumerate or magnesiumstearate may be used. Suitable amounts of lubricants are about 0-5% byweight, about 1-4% by weight and about 2-3% by weight.

Coatings

Coatings protect tablet ingredients from deterioration by moisture inthe air and make large or unpleasant-tasting tablets easier to swallow.Any conventional coating material, such as different grades of Opadrymay be used. Opadry is a mixture consisting of mainly hypromellose,macrogol 400 and Polysorbate 80. Any conventional coating method, likespraying may be used. Colors are sometimes added to improve theappearance of a tablet. Color consistency is important as it allows easyidentification of a medication. Some coatings are therefore coloredusing Opadry Blue or Opadry White, wherein titanium dioxide is the whitecolor agent.

In another embodiment, there is provided a composition, for use intherapy.

In another embodiment, there is provided a composition, for use in thetreatment of proliferative disorders. Typically, said proliferativedisorder is selected from tumors and cancers, including, but not limitedto, neurofibromatosis, tuberous sclerosis, hemangiomas andlymphangiogenesis, cervical, anal and oral cancers, eye or ocularcancer, stomach cancer, colon cancer, bladder cancer, rectal cancer,liver cancer, pancreas cancer, lung cancer, breast cancer, cervix utericancer, corpus uteri cancer, ovary cancer, prostate cancer, testiscancer, renal cancer, brain cancer, cancer of the central nervoussystem, head and neck cancer, throat cancer, skin melanoma, acutelymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma,Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma,small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma,hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer,esophageal cancer, larynx cancer, lymphoma, multiple myeloma; cardiachypertrophy, age-related macular degeneration and diabetic retinopathy.

More typically said proliferative disorder is selected from newlydiagnosed adults with Philadelphia chromosome-positive (Ph+) chronicmyeloid leukemia (CML) in chronic phase; adults with chronic,accelerated, or myeloid or lymphoid blast phase Ph+CML with resistanceor intolerance to prior therapy including imatinib; adults withPhiladelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL)with resistance or intolerance to prior therapy.

In another embodiment of this aspect, there is provided a compositionof, said composition is provided during food intake.

In another aspect, there is provided a method of treating proliferativedisorder in a patient in need thereof, comprising administering atherapeutically effective amount of a composition according to thepresent disclosure. Said proliferative disorder is typically selectedfrom tumors and cancers including, but not limited to,neurofibromatosis, tuberous sclerosis, hemangiomas andlymphangiogenesis, cervical, anal and oral cancers, eye or ocularcancer, stomach cancer, colon cancer, bladder cancer, rectal cancer,liver cancer, pancreas cancer, lung cancer, breast cancer, cervix utericancer, corpus uteri cancer, ovary cancer, prostate cancer, testiscancer, renal cancer, brain cancer, cancer of the central nervoussystem, head and neck cancer, throat cancer, skin melanoma, acutelymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma,Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma,small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma,hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer,esophageal cancer, larynx cancer, lymphoma, multiple myeloma; cardiachypertrophy, age-related macular degeneration and diabetic retinopathy.

Said proliferative disorder is more typically selected from newlydiagnosed adults with Philadelphia chromosome-positive (Ph+) chronicmyeloid leukemia (CML) in chronic phase; adults with chronic,accelerated, or myeloid or lymphoid blast phase Ph+CML with resistanceor intolerance to prior therapy including imatinib; adults withPhiladelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL)with resistance or intolerance to prior therapy.

The desired dose is conveniently presented in a single dose or as adivided dose administered at appropriate intervals, for example as two,three, four or more doses per day. Dependent on the need of thetreatment and/or prevention, the desired dose may also be, for example,once every two days, once every three days, or even once a week.

The composition is conveniently administered in unit dosage form; forexample containing 20 to 140 mg, conveniently as 20, 50, 70, 80, 100, or140 mg of active ingredient per unit dosage form.

Pharmaceutical compositions include but are not limited to thosesuitable for oral, rectal, nasal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (includingintramuscular, subcutaneous and intravenous) administration or in a formsuitable for administration by inhalation or insufflation. Thecompositions may, where appropriate, be conveniently presented indiscrete dosage units and may be prepared by any of the methods wellknown in the art of pharmacy. Pharmaceutical compositions suitable fororal administration are conveniently presented as discrete units such ascapsules, cachets or tablets, each containing a predetermined amount ofthe active substance.

Tablets for oral administration may contain conventional excipients suchas binding agents, fillers, lubricants, disintegrants, or wettingagents. The tablets may be coated according to methods well known in theart.

The following examples are provided to illustrate various embodiments ofthe disclosure and shall not be considered as limiting in scope.

By the phrase “reference listed drug” is meant the approved drug productSprycel 100 mg to which new generic versions are compared to show thatthey are bioequivalent. By designating a single reference listed drug asthe standard to which all generic versions must be shown to bebioequivalent, FDA hopes to avoid possible significant variations amonggeneric drugs and their brand name counterpart.

EXAMPLES Example 1

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.00propanediol solvate Mannitol (Roquette Filler/Binder 255.00 200 SD)Microcrystalline Filler/Binder 50.00 cellulose CroscarmelloseDisintegrant 50.00 sodium Silica colloidal Glidant 10.00 anhydrousSodium Stearyl Lubricant 20.00 fumerate Core tablet weight 500 Opadrywhite Cosmetic coat 10.00 Film coated tablet 510 weight

Example 2

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00propanediol solvate Mannitol (Roquette Filler/Binder 280.60 200 SD)Microcrystalline Filler/Binder 48.00 cellulose CroscarmelloseDisintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous SodiumStearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry whiteCosmetic coat 10.00 Film coated tablet 490 weight

Example 3

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00propanediol solvate Mannitol (Roquette Filler/Binder 280.60 500 DC)Microcrystalline Filler/Binder 48.00 cellulose CroscarmelloseDisintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous SodiumStearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry whiteCosmetic coat 10.00 Film coated tablet 490 weight

Example 4

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00propanediol solvate Mannitol (Roquette Filler/Binder 164.30 200 SD)Microcrystalline Filler/Binder 164.30 cellulose CroscarmelloseDisintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous SodiumStearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry whiteCosmetic coat 10.0 Film coated tablet 490 weight

Example 5

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Mannitol (Roquette Filler/Binder 254.00 Pearlitol200 SD) Microcrystalline Filler/Binder 44.00 cellulose Silica colloidalGlidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Coretablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet450 weight

Example 6

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Calcium Phosphate Filler/Binder 44.00 dibasicanhydrous Microcrystalline Filler/Binder 254.00 cellulose Silicacolloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerateCore tablet weight 440 Opadry white Cosmetic coat 10.00 Film coatedtablet 450 weight

Example 7

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Isomalt Filler/Binder 44.00 MicrocrystallineFiller/Binder 254.00 cellulose Silica colloidal Glidant 8.80 anhydrousSodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadrywhite Cosmetic coat 10.00 Film coated tablet 450 weight

Example 8

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Isomalt Filler/Binder 254.00 MicrocrystallineFiller/Binder 44.00 cellulose Silica colloidal Glidant 8.80 anhydrousSodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadrywhite Cosmetic coat 10.00 Film coated tablet 450 weight

Example 9

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Isomalt Filler/Binder 245.20 MicrocrystallineFiller/Binder 44.00 cellulose Croscarmellose Disintegrant 8.80 Silicacolloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerateCore tablet weight 440 Opadry white Cosmetic coat 10.00 Film coatedtablet 450 weight

Example 10

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Isomalt Filler/Binder 125.90 Mannitol (Pearlitol 200Filler/Binder 125.90 SD) Microcrystalline Filler/Binder 44.00 celluloseCroscarmellose Disintegrant 2.20 Silica colloidal Glidant 8.80 anhydrousSodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadrywhite Cosmetic coat 10.00 Film coated tablet 450 weight

Example 11

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60propanediol solvate Isomalt Filler/Binder 125.90 Mannitol (Pearlitol 200Filler/Binder 125.90 SD) Microcrystalline Filler/Binder 44.00 celluloseCroscarmellose Disintegrant 2.20 Silica colloidal Glidant 8.80 anhydrousSodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadrywhite Cosmetic coat 10.00 Film coated tablet 450 weight

Example 12

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.6propanediol solvate Mannitol (Pearlitol 200 Filler/Binder 72.0 SD)Mannitol (Pearlitol 300 Filler/Binder 72.0 DC) Isomalt Filler/Binder96.8 Microcrystalline Filler/Binder 44.0 cellulose CroscarmelloseDisintegrant 13.2 sodium Silica colloidal Glidant 8.8 anhydrous SodiumStearyl Lubricant 17.6 fumerate Core tablet weight 440 Opadry whiteCosmetic coat 10.0 Film coated tablet 450 weight

Example 13

A tablet was prepared based on the following recipe and directcompression:

Component Function mg/tablet Dasatinib 1,2- Drug substance 115.6propanediol solvate Mannitol (Pearlitol 200 Filler/Binder 77.0 SD)Mannitol (Pearlitol 300 Filler/Binder 77.0 DC) Isomalt Filler/Binder100.0 Microcrystalline Filler/Binder 44.0 cellulose Silica colloidalGlidant 8.8 anhydrous Sodium Stearyl Lubricant 17.6 fumerate Core tabletweight 440 Opadry white Cosmetic coat 10.0 Film coated tablet 450 weight

The tablets prepared above (non-coated) were subjected to a dissolutiontest, a USP Type 2 in 0.01 M hydrochloric acid at about 37° C. and about75 RPM, or as per Ph. Eur. 2.9.3. apparatus II (paddles), and theresults are shown in FIG. 1. The results are representative for thepresent disclosure.

Example 14

Tablets of Example 12 and 13 were manufactured using the followingprocess

The mannitol (Pearlitol 200 SD), mannitol (Pearlitol 300 DC), isomalt,microcrystalline cellulose, croscarmellose sodium and aerosil 200 weretransferred to a suitably sized mixing vessel and blended. The resultingexcipient blend mixture was then screened. The active component,dasatinib 1,2-propanediol solvate, was screened and added to the blendmixture in a suitably sized mixing vessel and blended. Sodium stearylfumarate was screened and added to the blend mixture. This was thenblended. The Dasatinib 1,2-propanediol solvate tablet blend wascompressed into tablets. The resultant tablets were then coated with anaqueous film coating (Opadry® White 03B28796 and sterile water forirrigation mixture).

Example 15

Tablets prepared according to Example 12 using the process of Example 14were used in a single centre, open-label, randomised, single dose, 3-waycrossover comparative PK study in healthy male subjects.

Each subject received the following regimens:

Route of Period Regimen Product Dose Administration A Tablet A 100 mgOral, Fasted A Tablet A 100 mg Oral, Fed

Plasma concentration data was tabulated and plotted for each subject forwhom concentrations are quantifiable. PK analysis of the concentrationtime data obtained was performed using appropriate non-compartmentaltechniques to obtain estimates of the following PK parameters, wherepossible:

-   -   Tlag: Time prior to the first measurable (non-zero)        concentration    -   Tmax: Time of maximum observed concentration    -   Cmax: Maximum observed concentration    -   C24: Plasma concentration at 24 h    -   AUC(0-last): Area under the curve from 0 time to the last        measurable concentration    -   AUC(0-24): Area under the curve from 0 time to 24 h post-dose    -   AUC(0-inf): Area under the curve from 0 time extrapolated to        infinity    -   Frel: Relative bioavailability    -   λz: Slope of the apparent elimination phase    -   T½: Apparent elimination half-life    -   MRT: mean residence time        Results

Variable Product Mean Median Min Max CV % Cmax A fasted 89 80 28 169 47A fed 100 85 36 214 49 AUCinf A fasted 342 331 146 588 33 A fed 413 390301 732 29

The PK variables Cmax, AUC(0-24) and AUC(0-∞) of the test formulation Ain the fasted state were compared to the historical PK data of thereference drug, Sprycel, obtained from the previous BA/BE studies. FIG.2 displays the results showing comparable bioavailability between thetest tablet A and the reference product, Sprycel® 100 mg.

Dependent FormRef Test Ratio_% Ref_(—) CI_90_Lower CI_90_UpperLn(AUCinf) Sprycel A fasted 93 73 119 Ln(Cmax) Sprycel A fasted 97 77121

The subject matter of U.S. Provisional Application Nos. 62/849,256 and62/909,913 is incorporated by reference in its entirety.

The references described herein are incorporated by reference in theirentirety to the extent necessary. In the event that there is adifference in meaning between the incorporated terms and the termsdisclosed herein and the terms of the related application, the meaningof the terms disclosed herein and the related application will control.

The subject matter of each of U.S. patent application Ser. No.16/700,310, filed Dec. 2, 2019; U.S. Provisional Application No.62/849,256, filed on May 17, 2019; and U.S. Provisional Application No.62/909,913, filed on Oct. 3, 2019 is incorporated by reference in itsentirety.

Those skilled in the art will also appreciate that various adaptationsand modifications of the preferred and alternative embodiments describedabove can be configured without departing from the scope and spirit ofthe disclosure. Therefore, it is to be understood that, within the scopeof the appended claims, the disclosure may be practiced other than asspecifically described herein.

The invention claimed is:
 1. A tablet for oral administration, comprising: dasatinib 1,2-propanediol solvate, dasatinib (R)-1,2 propanediol solvate, dasatinib (S)-1,2-propanediol solvate or a combination thereof; at least one pharmaceutically acceptable excipient; and a coating layer; wherein the tablet releases at least about 70% of the dasatinib within 20 minutes when the tablet is tested in a USP Type 2 in 500 mL of 0.01 M hydrochloric acid at about 370 C. and about 75 RPM.
 2. The tablet of claim 1, comprising dasatinib 1,2-propanediol solvate.
 3. The tablet of claim 1, comprising dasatinib (R)-1,2-propanediol solvate.
 4. The tablet of claim 1, comprising dasatinib (S)-1,2-propanediol solvate.
 5. The tablet of claim 1, wherein the amount of dasatinib is equivalent to 20, 50, 70, 80, 100, or 140 mg of dasatinib.
 6. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder selected from a group consisting of mannitol, microcrystalline cellulose, lactose, isomalt, or a mixture thereof.
 7. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder and the at least one filler/binder is present in an amount of from about 20% to about 90% by weight of the tablet.
 8. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder and the at least one filler/binder is present in an amount of from about 30% to about 80% by weight of the tablet.
 9. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant selected from a group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, or a mixture thereof.
 10. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant and the disintegrant is present in an amount of from about 0.5% to about 10% by weight of the tablet.
 11. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant and the disintegrant is present in an amount of from about 2% to about 10% by weight of the tablet.
 12. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant selected from a group consisting of anhydrous colloidal silica.
 13. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant and the glidant is present in an amount of from about 0% to about 5% by weight of the tablet.
 14. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant and the glidant is present in an amount of from about 1 to about 4% by weight of the tablet.
 15. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant selected from a group consisting of sodium stearyl fumerate, magnesium stearate, or a mixture thereof.
 16. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant and the lubricant is present in an amount of from about 0% to about 5% by weight.
 17. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant and the lubricant is present in an amount of from about 1% to about 4% by weight.
 18. The tablet of claim 1, wherein the coating layer comprises glyceryl monostearate, hypromellose, poly(vinyl alcohol), polyethylene glycol, polysorbate 80, sodium laurylsulfate, talc, titanium dioxide, or a combination thereof.
 19. The tablet of claim 1, wherein the coating layer is present in an amount of from about 1.9% to about 2.2% by weight of the tablet.
 20. The tablet of claim 1, wherein the tablet exhibits (a) a 90% Confidence Interval for the ratio of the mean AUC (0-∞) which is between 73% and 125%; and (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 77% and 125%; and wherein the ratio of the mean refers to an observable of the tablet for oral administration versus a reference listed drug comprising dasatinib monohydrate.
 21. The tablet of claim 1, wherein the tablet exhibits (a) a 90% Confidence Interval for the ratio of the mean AUC (0-∞) which is between 73% and 125%; and (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 77% and 125%; and wherein the ratio of the mean refers to an observable of the tablet for oral administration versus a reference listed drug comprising dasatinib monohydrate; and wherein the 90% Confidence Interval for the ratio of the mean AUC (0-∞) is established by excluding subjects with AUC (0-∞) less than 5% of the reference listed drug.
 22. A method of treating a proliferative disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a composition according to claim 5; wherein said proliferative disorder in a patient is newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+CML with resistance or intolerance to prior therapy including imatinib; or adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy. 